Robbins Neoplasia PDF

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See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Neoplasia 7 CHAPTER CONTENTS Nomenclature 268 Self-Sufficiency in Growth Signals: Epigenetic Changes 319 Benign Tumors 268 Oncogenes 284 Noncoding RNAs and Cancer 320 Malignant Tumors 268 Oncoproteins and Cell Growth 286 Molecular Basis of Multistep Mixed Tumors 269 Insensitivity to Growth Inhibition: Tumor Carcinogenesis 320 Characteristics of Benign and Suppressor Genes 291 Carcinogenic Agents and Their Malignant Neoplasms 270 Growth-Promoting Metabolic Alterations: Cellular Interactions 320 Differentiation and Anaplasia 270 The Warburg Effect 299 Chemical Carcinogenesis 321 Metaplasia, Dysplasia, and Carcinoma In Evasion of Cell Death 302 Direct-Acting Carcinogens 322 Situ 272 Limitless Replicative Potential: The Stem Indirect-Acting Carcinogens 322 Local Invasion 273 Cell–Like Properties of Cancer Radiation Carcinogenesis 323 Metastasis 273 Cells 303 Ultraviolet Rays 323 Pathways of Spread 274 Angiogenesis 305 Ionizing Radiation 323 Epidemiology of Cancer 277 Invasion and Metastasis 306 Microbial Carcinogenesis 323 The Global Impact of Cancer 277 Invasion of Extracellular Matrix 307 Oncogenic RNA Viruses 324 Environmental Factors 278 Vascular Dissemination, Homing, and Oncogenic DNA Viruses 324 Age 278 Colonization 308 Helicobacter pylori 327 Acquired Predisposing Evasion of Immune Surveillance 309 Clinical Aspects of Neoplasia 328 Conditions 279 Tumor Antigens 309 Clinical Manifestations 328 Genetic Predisposition and Interactions Antitumor Effector Mechanisms 311 Grading and Staging of Tumors 330 Between Environmental and Inherited Mechanisms of Immune Evasion by Laboratory Diagnosis of Cancer 331 Factors 281 Cancers 311 Molecular Profiles of Tumors: The Future of Molecular Basis of Cancer: Role of Genomic Instability 314 Cancer Diagnostics 334 Genetic and Epigenetic Cancer-Enabling Inflammation 315 Tumor Markers 335 Alterations 281 Dysregulation of Cancer-Associated Cellular and Molecular Hallmarks of Genes 316 Cancer 284 Chromosomal Changes 316 Cancer is the second leading cause of death in the United In this chapter, we describe the vocabulary of tumor States; only cardiovascular diseases exact a higher toll. Even biology and pathology and then review the morphologic more agonizing than the mortality rate is the emotional characteristics that define neoplasia and allow benign and and physical suffering inflicted by cancers. Patients and malignant tumors to be identified and distinguished. Also the public often ask, “When will there be a cure for this reviewed is the epidemiology of cancer, which provides scourge?” The answer to this simple question is difficult a measure of the impact of cancer on human populations because cancer is not one disease but many disorders as well as clues to its environmental causes, insights that with widely different pathogeneses, natural histories, and have led to effective prevention campaigns against certain responses to treatments. Some cancers, such as Hodgkin cancers. Building on this foundation, we then discuss the lymphoma, are curable, whereas others, such as pancreatic biologic properties of tumors and the molecular basis of adenocarcinoma, are virtually always fatal. The only hope carcinogenesis, emphasizing the critical role that genetic for controlling cancer lies in learning more about its causes alterations play in the development of neoplasia. Finally, and pathogenesis. Fortunately, great strides have been made we turn to cancer diagnosis, focusing on new technologies in understanding its molecular basis, and some good news that are helping to direct the use of cancer drugs that are has emerged: cancer mortality for both men and women targeted at particular molecular lesions. Throughout, we in the United States declined during the last decade of the give examples of new analytic methods and therapies that 20th century and has continued its downward course in the are not only changing our approach to cancer treatment but 21st century. also providing new insights into cancer pathophysiology. 267 268 CHAPTER 7 Neoplasia when benign tumors occur in vulnerable locations such as NOMENCLATURE the brain; here, even “benign” tumors may cause significant morbidity and are sometimes even fatal. Neoplasia means “new growth,” and the collection of cells Naming of benign tumors of mesenchymal cells is relatively and stroma composing new growths are referred to as simple; in general, the suffix “-oma” is attached to the name neoplasms. Tumor originally described swelling caused by of the cell type from which the tumor arises. Thus a benign inflammation, but is now equated with neoplasm. Oncology tumor of fibroblast-like cells is called a fibroma, a benign (Greek oncos = tumor) is the study of tumors or neoplasms. cartilaginous tumor is a chondroma, and so on. The nomen- Although physicians know what they mean when they use clature of benign epithelial tumors is more complex; some the term neoplasm, it has been difficult to develop a precise are classified based on their cell of origin, others on their definition. In the modern era, a neoplasm is defined as a microscopic appearance, and still others on their macroscopic genetic disorder of cell growth that is triggered by acquired architecture. Adenoma is applied to benign epithelial neoplasms or less commonly inherited mutations affecting a single cell derived from glandular tissues even if the tumor cells fail and its clonal progeny. As discussed later, these causative to form glandular structures. Thus, a benign epithelial mutations alter the function of particular genes and give neoplasm that arises from renal tubular cells and forms tightly the neoplastic cells a survival and growth advantage, result- clustered glands and a mass of adrenal cortical cells growing ing in excessive proliferation that is independent of physi- as a solid sheet are both referred to as adenomas. Benign ologic growth signals and controls. epithelial neoplasms producing fingerlike or warty projections All tumors are composed of two components: (1) neo- from epithelial surfaces are called papillomas, whereas those plastic cells that constitute the tumor parenchyma and (2) that form large cystic masses, such as in the ovary, are referred reactive stroma made up of connective tissue, blood vessels, to as cystadenomas. Some tumors produce papillary projections and cells of the adaptive and innate immune system. The that protrude into cystic spaces and are called papillary classification of tumors and their biologic behavior are based cystadenomas. When a neoplasm—benign or malignant— primarily on the parenchymal component, but their growth produces a grossly visible projection above a mucosal surface, and spread are critically dependent on their stroma. In some for example, into the gastric or colonic lumen, it is termed a tumors, connective tissue is scant, and the neoplasm is soft polyp. If the polyp has glandular tissue, it is called an adeno- and fleshy. In others, parenchymal cells stimulate the forma- matous polyp (Fig. 7.1). tion of abundant collagenous stroma, referred to as desmo- plasia. Some desmoplastic tumors—for example, some cancers Malignant Tumors of the female breast—are stony hard or scirrhous. Malignant tumors can invade and destroy adjacent struc- tures and spread to distant sites (metastasize). Malignant Benign Tumors tumors are collectively referred to as cancers, derived from Benign tumors remain localized at their site of origin and the Latin word for crab, because they tend to adhere to any are generally amenable to surgical removal. Predictably, part that they seize on in an obstinate manner. Not all cancers the patient generally survives. Exceptions arise, however, pursue a deadly course; some are discovered at early stages A B Figure 7.1 Colonic polyp. (A) An adenomatous (glandular) polyp is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. (B) Gross appearance of several colonic polyps.  Nomenclature 269 that allow for surgical excision, and others are cured with systemically administered drugs or therapeutic antibodies. Nevertheless, the designation “malignant” always raises a red flag. The nomenclature of malignant tumors follows essentially the same schema used for benign neoplasms, with certain additions. Malignant tumors arising in solid mesenchymal tissues are usually called sarcomas (Greek sar = fleshy; e.g., fibrosarcoma and chondrosarcoma), whereas those arising from blood-forming cells are designated leukemias (literally, white blood) or lymphomas (tumors of lymphocytes or their precursors). Malignant neoplasms of epithelial cell origin are called carcinomas. Carcinomas may be further qualified. In squamous cell carcinoma the tumor cells resemble stratified squamous epithelium, whereas in adenocarcinoma the neo- plastic epithelial cells grow in a glandular pattern. Sometimes the tissue or organ of origin can be identified and is added as a descriptor, as in renal cell adenocarcinoma or broncho- Figure 7.2 Mixed tumor of the parotid gland. Small nests of epithelial genic squamous cell carcinoma. In approximately 2% of cells and myxoid stroma forming cartilage and bone (an unusual feature) cases, cancers are composed of cells of unknown origin and are present in this field. (Courtesy Dr. Vicky Jo, Department of Pathology, must be designated merely as undifferentiated malignant Brigham and Women’s Hospital, Boston, Mass.) tumors. Mixed Tumors In most neoplasms, all parenchymal cells closely resemble Such cells can differentiate into any cell type found in the one another, but in some types of tumors more than one body and so, not surprisingly, may give rise to neoplasms line of differentiation is evident, creating distinct subpopula- that contain, in a helter-skelter fashion, bone, epithelium, tions of cells. A classic example is the mixed tumor of the muscle, fat, nerve, and other tissues. A particularly common salivary gland, which contains epithelial components scat- pattern is seen in the ovarian cystic teratoma (dermoid cyst), tered within a myxoid stroma that may contain islands of which differentiates principally along ectodermal lines to cartilage or bone (Fig. 7.2). All of these elements arise from create a cystic tumor lined by squamous epithelium that is a single neoplastic clone capable of producing both epithelial replete with hair, sebaceous glands, and tooth structures and mesenchymal cells; thus the preferred designation of (Fig. 7.3). this neoplasm is pleomorphic adenoma. The great majority of The nomenclature of the more common types of tumors neoplasms, including mixed tumors, are composed of cells is presented in Table 7.1. Included in this list are some from a single germ layer (mesoderm, endoderm, or ecto- inappropriate but deeply entrenched names. For instance, derm). An exception is a tumor called a teratoma, which the benign-sounding designations lymphoma, melanoma, contains recognizable mature or immature cells or tissues mesothelioma, and seminoma are used for malignant belonging to more than one germ cell layer (and sometimes neoplasms. Alternatively, ominous-sounding terms are all three). Teratoma originates from totipotential germ cells applied to some trivial lesions. Hamartomas are disorganized that are normally present in the ovary and testis and masses composed of cells indigenous to the involved tissue. sometimes also found in abnormal midline embryonic rests. Once thought to be a developmental malformation unworthy A B Figure 7.3 (A) Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and a tooth. (B) Microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow). 270 CHAPTER 7 Neoplasia Table 7.1 Nomenclature of Tumors of the “-oma” designation, most hamartomas have clonal Tissue of chromosomal aberrations that are acquired through somatic Origin Benign Malignant mutation and on this basis are now considered benign Composed of One Parenchymal Cell Type neoplasms. Choristoma is the term applied to a heterotopic (misplaced) rest of cells. For example, a small nodule of Tumors of Mesenchymal Origin well-developed, normally organized pancreatic tissue may Connective tissue Fibroma Fibrosarcoma be found in the submucosa of the stomach or small intestine. and derivatives Lipoma Liposarcoma The term choristoma, suggesting a neoplasm, imparts a Chondroma Chondrosarcoma gravity to these lesions that far exceeds their actual Osteoma Osteogenic sarcoma significance. Vessels and Surface Coverings Blood vessels Hemangioma Angiosarcoma Lymph vessels Lymphangioma Lymphangiosarcoma CHARACTERISTICS OF BENIGN AND Mesothelium Benign fibrous Mesothelioma MALIGNANT NEOPLASMS tumor Brain coverings Meningioma Invasive meningioma The differentiation between benign and malignant tumors is one of the most important distinctions a pathologist can Blood Cells and Related Cell Types make, as nothing is more important to an individual with Hematopoietic cells Leukemias a tumor than being told, “It is benign.” Although an innocent Lymphoid tissue Lymphomas face may mask an ugly nature, benign and malignant tumors Muscle usually can be distinguished on the basis of various histologic and anatomic features (described later). Malignant tumors Smooth Leiomyoma Leiomyosarcoma also tend to grow more rapidly than benign tumors, but Striated Rhabdomyoma Rhabdomyosarcoma there are so many exceptions that growth rate is not a reliable Tumors of Epithelial Origin discriminator between benignity and malignancy. In fact, Stratified squamous Squamous cell Squamous cell even cancers exhibit remarkably varied growth rates, from papilloma carcinoma slow-growing tumors associated with survival for many Basal cells of skin Basal cell carcinoma years, often without treatment, to rapidly growing tumors or adnexa that may be lethal within months or weeks. Melanocytes Nevus Malignant melanoma Epithelial lining of Adenoma Adenocarcinoma Differentiation and Anaplasia glands or ducts Papilloma Papillary carcinomas Cystadenoma Cystadenocarcinoma Differentiation refers to the extent to which neoplastic Respiratory Bronchial adenoma Bronchogenic parenchymal cells resemble the corresponding normal passages carcinoma parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia. In general, benign Renal epithelium Renal tubular Renal cell carcinoma adenoma tumors are well differentiated (Figs. 7.4 and 7.5). The neoplastic cells of a lipoma, a proliferation of benign adi- Liver cells Hepatic adenoma Hepatocellular carcinoma pocytes, may so closely resemble normal adipocytes as to be unrecognizable as a tumor by microscopic examination. Urinary tract Transitional cell Transitional cell Only the growth of these cells into a discrete mass discloses epithelium papilloma carcinoma (transitional epithelium) Placenta epithelium Hydatidiform mole Choriocarcinoma Testicular Seminoma epithelium (germ Embryonal cells) carcinoma More Than One Neoplastic Cell Type—Mixed Tumors, Usually Derived From One Germ Cell Layer Salivary glands Pleomorphic Malignant mixed adenoma (mixed tumor of salivary tumor of salivary gland origin origin) Renal anlage Wilms tumor More Than One Neoplastic Cell Type Derived From More Than One Germ Cell Layer—Teratogenous Totipotential cells Mature teratoma, Immature teratoma, in gonads or in dermoid cyst teratocarcinoma embryonic rests Figure 7.4 Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.  Characteristics of benign and malignant neoplasms 271 Figure 7.5 Benign tumor (adenoma) of the thyroid. Note the normal- Figure 7.6 Well-differentiated squamous cell carcinoma of the skin. The looking (well-differentiated), colloid-filled thyroid follicles. (Courtesy Dr. tumor cells are strikingly similar to normal squamous epithelial cells, with Trace Worrell, University of Texas Southwestern Medical School, Dallas, intercellular bridges and nests of keratin pearls (arrow). (Courtesy Dr. Trace Tex.) Worrell, University of Texas Southwestern Medical School, Dallas, Tex.) their neoplastic nature. One may get so close to the tree Pleomorphism. Pleomorphism refers to variation in cell that one loses sight of the forest. In well-differentiated benign size and shape. Thus, cells within the same tumor are tumors, mitoses are usually rare and are of normal not uniform, but range from small cells with an undif- configuration. ferentiated appearance to tumor giant cells many times By contrast, most malignant neoplasms exhibit mor- larger than their neighbors. Some tumor giant cells possess phologic alterations that betray their potential for aggres- only a single huge polymorphic nucleus, while others sive behavior. In well-differentiated tumors, these features may have two or more large, hyperchromatic nuclei (Fig. may be quite subtle. Well-differentiated adenocarcinomas 7.9). These giant cells are not to be confused with inflam- of the thyroid, for example, form normal-appearing follicles, matory Langhans or foreign body giant cells, which are and some squamous cell carcinomas contain cells that appear derived from macrophages and contain many small, identical to normal squamous epithelial cells (Fig. 7.6). The normal-appearing nuclei. malignant nature of such tumors is revealed by invasion Abnormal nuclear morphology. Characteristically, cancer of adjacent tissues and their ability to metastasize. At the cells have nuclei that are disproportionately large, with other end of the spectrum lie highly anaplastic, poorly a nuclear-to-cytoplasm ratio that may approach 1 : 1 differentiated tumors exhibiting little or no evidence of instead of the normal 1 : 4 to 1 : 6. The nuclear shape is differentiation (Fig. 7.7), a morphologic appearance that is variable and often irregular, and the chromatin is often highly predictive of malignant behavior. In between these coarsely clumped and distributed along the nuclear two extremes lie tumors that are loosely referred to as moderately well differentiated (Fig. 7.8). In addition to anaplasia, cancer cells often exhibit other telltale morphologic changes: Figure 7.8 Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor, the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered moderately well differentiated because gland formation is seen. The Figure 7.7 Anaplastic tumor showing cellular and nuclear variation in size malignant glands have invaded the muscular layer of the colon. (Courtesy and shape. The prominent cell in the center field has an abnormal tripolar Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, spindle. Tex.) 272 CHAPTER 7 Neoplasia hormone, insulin, glucagon, and other hormones, giving rise to paraneoplastic syndromes (described later). Metaplasia, Dysplasia, and Carcinoma In Situ These terms describe morphologically recognizable changes in differentiation that variously represent an adaptation to chronic injury (metaplasia), a premalignant change (dys- plasia), or a cancer that has yet to invade (carcinoma in situ). Metaplasia is defined as the replacement of one type of cell with another type (Chapter 2). Metaplasia is nearly always found in association with tissue damage, repair, and regeneration. Often the replacing cell type is better suited to some alteration in the local environment. For example, in Barrett esophagus, gastroesophageal reflux damages Figure 7.9 Pleomorphic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, the squamous epithelium of the esophagus, leading to its hyperchromatic nuclei, and tumor giant cells. (Courtesy Dr. Trace Worrell, replacement by glandular (gastric or intestinal) epithelium University of Texas Southwestern Medical School, Dallas, Tex.) better suited to an acidic environment. Unfortunately, the metaplastic epithelium is prone to malignant transforma- tion. The same is true of squamous metaplasia of the membrane or more darkly stained than normal (hyper- bronchial epithelium in chronic smokers, often a prelude chromatic). Abnormally large nucleoli are also commonly to the development of lung cancer. seen. Dysplasia is a term that literally means “disordered Mitoses. Unlike benign tumors and some well-differentiated growth.” It is encountered principally in epithelial cells malignant neoplasms, undifferentiated cancers often and is recognized on the basis of several morphologic contain many cells in mitosis, reflecting their high rate changes. Dysplastic cells may exhibit considerable of proliferation. The presence of mitoses, however, does pleomorphism and often contain large hyperchromatic not equate with malignancy. For example, cells in mitosis nuclei with a high nuclear-to-cytoplasmic ratio. Dysplastic are often seen in normal tissues exhibiting rapid turnover, epithelial surfaces also typically show architectural disar- such as the epithelial lining of the gut and nonneoplastic ray and a loss of orderly differentiation. For example, in proliferations such as hyperplasias. More important as dysplastic squamous epithelium the normal progressive a morphologic feature of malignancy are atypical, bizarre maturation of tall cells in the basal layer to flattened mitotic figures (see Fig. 7.8). squames on the surface may fail in part or entirely, leading Loss of polarity. In addition to cytologic abnormalities, to replacement of the epithelium by basal-like cells with the orientation of anaplastic cells with respect to each hyperchromatic nuclei. In addition, mitotic figures are other or to supporting structures like basement mem- more abundant than in the normal squamous epithelium branes is markedly disturbed. Sheets or large masses of and may be seen throughout dysplastic epithelium, rather tumor cells grow in a disorganized fashion. than being confined to the basal layer, as is the normal Other changes. While growing tumor cells must have a case. blood supply, the vascular stroma is often insufficient; Carcinoma in situ. When dysplasia is severe and involves as a result, many rapidly growing cancers develop areas the full thickness of the epithelium but the lesion does of ischemic necrosis. not penetrate the basement membrane, it is referred to as carcinoma in situ (Fig. 7.10). Carcinoma in situ is often As one might surmise, well-differentiated transformed seen in the skin, breast, bladder, and uterine cervix. In cells have a greater likelihood of retaining the functional situ epithelial cancers display all of the cytologic features capabilities of their normal counterparts. Benign tumors are of malignancy and unless treated have high probability almost always well differentiated and often retain normal of progression to invasive cancers. functions, as do many well-differentiated cancers. Thus, well-differentiated tumors of endocrine glands frequently Dysplastic changes are often found adjacent to foci of secrete hormones characteristic of their origin into the blood, invasive carcinoma, and in some situations, such as in the where they can be detected and quantified to diagnose and cervix, severe epithelial dysplasia or carcinoma in situ follow the response of such tumors to treatment. Similarly, frequently antedates the appearance of cancer. Moreover, well-differentiated squamous cell carcinomas synthesize some mutations associated with full-blown cancer (described keratin, and well-differentiated hepatocellular carcinomas later) may be present in even “mild” dysplasias. Nevertheless, elaborate bile. By contrast, highly anaplastic undifferentiated although dysplasia may be a precursor to malignant tumors typically lose the specialized functional activities of transformation, it does not always progress to cancer. With their tissue of origin, but sometimes acquire new and unan- removal of inciting causes, even moderately severe dysplasias ticipated functions. Thus some malignant tumors express may be completely reversible. Even carcinoma in situ may fetal proteins that are not produced by their normal adult persist for years before it becomes invasive. As discussed counterparts, while others express proteins that are normally later, cancers arise by accumulation of mutations, and the found only in other types of cells. For example, bronchogenic time interval for evolution of full-blown cancers from in carcinomas may produce corticotropin, parathyroid-like situ lesions relates most likely to the time required for  Characteristics of benign and malignant neoplasms 273 A B Figure 7.10 (A) Carcinoma in situ. Low-power view shows that the epithelium is entirely replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact, and there is no tumor in the subepithelial stroma. (B) High-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. accumulation of all the mutations that are needed to induce the surface of the skin. This invasiveness makes their a fully malignant phenotype. Finally, it should be noted complete surgical resection difficult or impossible, and even that while dysplasia often occurs in metaplastic epithelium, if the tumor appears well circumscribed it is necessary to not all metaplastic epithelium is dysplastic. remove a large margin of adjacent, apparently normal tissue to ensure complete local excision. Local Invasion Metastasis The growth of cancers is accompanied by progressive invasion, destruction of surrounding tissue, and eventually Metastasis is defined as the spread of a tumor to sites that systemic spread, whereas nearly all benign tumors grow are physically discontinuous with the primary tumor, an as cohesive, expansile masses that remain localized to their site of origin and lack the capacity to invade or metastasize to distant sites. Because benign tumors grow and expand slowly, they usually develop a rim of compressed fibrous tissue called a capsule that separates them from the sur- rounding normal tissue. The tumor capsule consists of extracellular matrix (ECM) deposited by stromal cells such as fibroblasts, which are activated by hypoxic damage resulting from the pressure of the expanding tumor. Such encapsulation creates a tissue plane that makes the tumor discrete, readily palpable, movable (nonfixed), and easily excisable by surgical enucleation (Fig. 7.11). There are a few A exceptions to this rule, however. For example, hemangiomas (benign neoplasms composed of tangled blood vessels) are often unencapsulated and permeate the site in which they arise (e.g., the dermis of the skin and the liver); when such lesions are extensive, they may be unresectable. In contrast, malignant tumors are, in general, poorly demarcated from the surrounding normal tissue and lack well-defined cleavage planes (Fig. 7.12). Slowly expanding malignant tumors may develop an apparently enclosing fibrous capsule and push along a broad front into adjacent normal structures. However, histologic examination of such “pseudoencapsulated” masses almost always shows rows of tumor cells penetrating the margin and infiltrating adjacent structures, a crablike pattern of growth that fits the popular image of cancer. B Next to the development of metastases, invasiveness Figure 7.11 Fibroadenoma of the breast. (A) The tan-colored, is the most reliable discriminator of malignant and benign encapsulated small tumor is sharply demarcated from the whiter breast tumors. Most malignant tumors do not recognize normal tissue. (B) Microscopic view shows that the fibrous capsule (right) delimits anatomic boundaries. Given time, they will penetrate the the tumor from the surrounding tissue. (B, Courtesy Dr. Trace Worrell, wall of the colon or uterus, for example, or fungate through University of Texas Southwestern Medical School, Dallas, Tex.) 274 CHAPTER 7 Neoplasia A B Figure 7.12 Invasive ductal carcinoma of the breast. (A) On cut section, the lesion is retracted and infiltrates the surrounding breast substance and would be stony hard on palpation. (B) Low-power microscopic view shows irregular infiltrative borders without a well-defined capsule and intense stromal reaction. (A, Courtesy Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, Tex.; B, Courtesy Dr. Susan Lester, Brigham and Women’s Hospital, Boston, Mass.) event that unequivocally marks a tumor as malignant. The spread of tumor cells on surgical instruments may occur—it invasiveness of cancers permits them to penetrate blood is the reason, for example, why biopsies of testicular masses vessels, lymphatics, and body cavities, providing the are never done—it is rare and not discussed further. opportunity for spread. All malignant tumors can metas- tasize, but some do so very infrequently. Examples include Seeding of Body Cavities and Surfaces. Seeding of body malignant neoplasms of the glial cells in the central nervous cavities and surfaces occurs when a malignant neoplasm system, called gliomas, and basal cell carcinomas of the skin, penetrates into a natural “open field” lacking physical both of which invade early in their course but rarely metas- barriers. Most often involved is the peritoneal cavity (Fig. tasize. It is evident then that the properties of invasiveness 7.13), but any body cavity—pleural, pericardial, subarach- and metastasis are separable. Blood cancers (leukemias and noid, and joint spaces—may be affected. Such seeding is lymphomas) are a special case. These tumors are derived particularly characteristic of carcinomas arising in the ovaries, from cells that normally have the capacity to enter the which often spread to peritoneal surfaces, producing a heavy bloodstream and travel to distant sites. As a result, leukemias cancerous coating. Remarkably, the tumor cells may remain and lymphomas (sometimes referred to as “liquid tumors”) confined to the surface of the abdominal viscera without are often disseminated at diagnosis and are always taken penetrating into the substance. Sometimes, mucus-secreting to be malignant, unlike all other tumors (so-called “solid” tumors), which are derived from cells that do not normally circulate in the bloodstream. Overall, approximately 30% of solid tumors (excluding skin cancers other than melanomas) present as metastatic disease. In general, the likelihood of metastasis of a solid tumor correlates with other features of malignancy, including lack of differentiation, aggressive local invasion, rapid growth, and large size. There are innumerable exceptions, however. Small, well-differentiated, slow-growing lesions sometimes metastasize widely; conversely, some rapidly growing, large lesions remain localized for years. Metastasis is thus a complex and unpredictable process that involves many factors relating to both invader and host (discussed later). Metastatic spread strongly reduces the possibility of cure; hence, short of prevention of cancer, no achievement would be of greater benefit to patients than an effective means to block metastasis, with the important caveat that many tumors that kill the patient have already spread by the time of initial diagnosis. Pathways of Spread Figure 7.13 Involvement of omentum by metastatic ovarian carcinoma. Dissemination of cancers occurs through three pathways: Innumerable nodules and more subtle “glazing” are evident due to seeding (1) direct seeding of body cavities or surfaces, (2) lymphatic by carcinoma cells via the peritoneal cavity. (Courtesy Dr. Sarah Hill, spread, and (3) hematogenous spread. Although iatrogenic Brigham and Women’s Hospital, Boston, Mass.)  Characteristics of benign and malignant neoplasms 275 because of variation in normal patterns of lymphatic drainage. In breast cancer, axillary lymph node examination is used to determine the prognosis and select the most suitable therapeutic options. To avoid the surgical morbidity associ- ated with a full axillary lymph node dissection, biopsy of sentinel nodes is often used to assess the presence or absence of metastatic lesions. A sentinel lymph node is defined as “the first node in a regional lymphatic basin that receives lymph flow from the primary tumor.” Sentinel node mapping can be done by injection of radiolabeled tracers or colored dyes, and examination of frozen sections of the sentinel lymph node performed during surgery can guide the surgeon to the appropriate therapy. Sentinel node examination has also been used to assess the spread of melanomas, colon cancers, and other tumors. In many cases the regional nodes serve as effective barriers Figure 7.14 Axillary lymph node with metastatic breast carcinoma. Note against further dissemination of the tumor, at least for a the aggregates of tumor cells within the substance of the node and the while. Conceivably, after arrest within the node the cells dilated lymphatic channel. (Courtesy Dr. Susan Lester, Brigham and may be destroyed by a tumor-specific immune response. Women’s Hospital, Boston, Mass.) The immune response to tumor cells or antigens in draining lymph nodes may lead to enlargement (hyperplasia) of the nodes. Thus, enlarged lymph nodes do not always harbor appendiceal carcinomas or ovarian carcinomas fill the metastases, which can be assessed definitively only by peritoneal cavity with a gelatinous neoplastic mass referred microscopic examination. to as pseudomyxoma peritonei. Hematogenous Spread. Hematogenous spread is typical Lymphatic Spread. Transport through lymphatic vessels of sarcomas but is also seen with carcinomas. In general, is the most common pathway for the initial dissemination histologic evidence of penetration of small vessels at the of carcinomas (Fig. 7.14). Sarcomas also sometimes use this site of the primary neoplasm is an ominous feature associated route. Tumors do not contain functional lymphatic vessels, with hematogenous metastasis. The involved vessels are but lymphatic vessels located at the margins of invading usually small veins, as arteries, with their thicker walls, are cancers are apparently sufficient for the lymphatic spread more resistant to penetration. Arterial spread may occur, of tumor cells. The pattern of spread follows the natural however, when tumor cells pass through pulmonary capil- routes of lymphatic drainage. For example, because carci- lary beds or pulmonary arteriovenous shunts or when nomas of the breast usually arise in the upper outer cancers in the lung (primary or metastatic) give rise to tumor quadrants, they generally disseminate first to the axillary emboli. lymph nodes and then to infraclavicular and supraclavicular Several factors influence the patterns of vascular metas- lymph nodes. Carcinomas of the lung arising in the major tasis. With venous invasion, the blood-borne tumor cells respiratory passages metastasize first to perihilar tracheo- often come to rest in the first capillary bed they encounter. bronchial and mediastinal lymph nodes. Local lymph nodes, Understandably, the liver and the lungs (Fig. 7.15) are most however, may be bypassed—so-called skip metastasis— frequently involved by hematogenous dissemination because possibly because microscopic metastases are missed or all portal area drainage flows to the liver and all caval blood A B Figure 7.15 Cancer metastasis. (A) Liver studded with metastatic cancer. (B) Microscopic view of lung metastasis. A colonic adenocarcinoma has formed a metastatic nodule in the lung. (B, Courtesy Dr. Shuji Ogino, Dana Farber Cancer Institute, Boston, Mass.) 276 CHAPTER 7 Neoplasia Table 7.2 Comparisons Between Benign and Malignant Tumors Characteristics Benign Malignant Differentiation/ Well differentiated; structure sometimes typical of tissue Some lack of differentiation (anaplasia); structure often anaplasia of origin atypical Rate of growth Usually progressive and slow; may come to a standstill or Erratic, may be slow to rapid; mitotic figures may be regress; mitotic figures rare and normal numerous and abnormal Local invasion Usually cohesive, expansile, well-demarcated masses that Locally invasive, infiltrating surrounding tissue; sometimes do not invade or infiltrate surrounding normal tissues may be misleadingly cohesive and expansile Metastasis Absent Frequent; more likely with large undifferentiated primary tumors flows to the lungs. Cancers arising in close proximity to the The distinguishing features of benign and malignant vertebral column often embolize through the paravertebral tumors are summarized in Table 7.2 and Fig. 7.16. Having plexus; this pathway produces frequent vertebral metastases completed our overview of the morphology and behavior from carcinomas of the thyroid and prostate. Nonetheless, of neoplasms, we now discuss the pathogenesis of neoplasia, many observations suggest that the location of the primary starting with clues gleaned from studies of the epidemiology tumor and its natural pathways of venous drainage do not of cancer. wholly explain the observed patterns of metastatic spread, which are often cancer-specific. Unfortunately, most cancers have not read pathology textbooks! The basis of tissue-specific patterns of metastasis is discussed later. KEY CONCEPTS Certain cancers have a curious propensity for growth CHARACTERISTICS OF BENIGN AND within large veins. Renal cell carcinoma often invades the MALIGNANT NEOPLASMS branches of the renal vein and then the renal vein itself, Benign and malignant tumors can be distinguished from one growing in a snakelike fashion up the inferior vena cava another based on the degree of differentiation, local invasiveness, until it sometimes reaches the right side of the heart. Simi- and distant spread. larly, hepatocellular carcinomas often penetrate portal and Benign tumors resemble the tissue of origin and are well dif- hepatic radicles and then grow into the main venous chan- ferentiated; malignant tumors are less well differentiated or nels. Remarkably, such intravenous growth may not be completely undifferentiated (anaplastic). accompanied by widespread metastasis. Endometrium Fallopian tube Tumor Ovary Vein BENIGN MALIGNANT (Leiomyoma) (Leiomyosarcoma) Small Noninvasive Large Locally invasive Well demarcated Nonmetastatic Poorly demarcated Metastatic Slow growing Well differentiated Rapidly growing with Poorly differentiated hemorrhage and necrosis Figure 7.16 Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of the same origin (leiomyosarcoma).  Epidemiology of cancer 277 1 in 6 of all deaths. Moreover, due to increasing population Benign tumors are more likely to retain functions of their cells size and age, cancer cases and cancer-related deaths of origin, whereas malignant tumors sometimes acquire unex- worldwide are projected to increase to 21.4 million and pected functions due to derangements in differentiation. 13.2 million, respectively by the year 2030. The major organ Benign tumors are slow growing, while malignant tumors generally sites affected and the estimated frequency of cancer deaths grow faster. in the United States are shown in Fig. 7.17. The most common Benign tumors are circumscribed and have a capsule; malignant tumors in men arise in the prostate, lung, and colon/rectum. tumors are poorly circumscribed and invade surrounding normal In women, cancers of the breast, lung, and colon/rectum tissues. are the most frequent. Cancers of the lung, female breast, Benign tumors remain localized at the site of origin; malignant prostate, and colon/rectum constitute more than 50% of tumors metastasize to distant sites. Carcinomas tend to spread cancer diagnoses and cancer deaths in the United States. via lymphatics, whereas sarcomas prefer the hematogenous route. Most longitudinal data pertaining to cancer incidence come from higher income countries, where age-adjusted death rates (deaths per 100,000 population) for many cancers EPIDEMIOLOGY OF CANCER have changed significantly over the years. In the last 50 years of the 20th century, the age-adjusted cancer death Study of cancer in defined populations has contributed rate increased significantly in both men and women. substantially to knowledge about its origins. Epidemiologic However, since 1995 the cancer incidence rate in men has studies have established the causative link between smoking been stable, and since 1990 the cancer death rate has and lung cancer, and comparison of diet and cancer rates decreased by approximately 20%. Similarly, the cancer in different regions of the world has linked diets high in incidence rate also stabilized in women in 1995, and the fat and low in fiber to colon cancer. It is hoped that additional cancer death rate has fallen by approximately 10% since insights into the causes of cancer will be obtained by studies 1991. Among men, nearly 80% of the decrease is accounted that relate particular environmental, racial (possibly heredi- for by lower death rates from lung, prostate, and colorectal tary), and cultural influences to specific neoplasms. The cancers; among women, nearly 60% of the decrease is due strong association of certain inflammatory and other diseases to reductions in death rates from breast and colorectal with cancer also provides clues to its pathogenesis. In the cancers. Decreased use of tobacco products is responsible following sections, we discuss the overall incidence of cancer for the reduction in lung cancer deaths, while improved and then review environmental and host factors that influ- detection and treatment are responsible for the decrease in ence the predisposition to cancer. death rates for colorectal, female breast, and prostate cancer. The last half-century has also seen a sharp decline in The Global Impact of Cancer deaths caused by cervical cancer in the United States. This decrease is largely attributable to the Papanicolaou (Pap) In 2018 it was estimated that there were over 9.5 million smear test, which enables detection of “precursor lesions” deaths caused by cancer worldwide, representing nearly (discussed later) and early, curable cancers. By contrast, A. 2019 ESTIMATED CANCER INCIDENCE BY SITE AND SEX B. 2019 ESTIMATED CANCER DEATHS BY SITE AND SEX Men 870,970 Women 891,480 Men 318,420 Women 282,500 Melanoma 6% of skin 5% Melanoma Oropharynx 4% of skin 3% Brain Lung, bronchus 24% 4% Thyroid 23% Lung, bronchus Lung, bronchus 13% Esophagus 4% 13% Lung, bronchus 15% Breast Pancreas 3% 30% Breast Liver, bile duct 7% 4% Liver, bile duct Kidney 5% 3% Kidney Pancreas 7% 8% Pancreas Colon and 9% 3% Pancreas Kidney 3% 8% Colon and rectum Colon and 9% 7% Colon and rectum Urinary 7% rectum rectum 5% Ovary bladder 3% Ovary Urinary bladder 4% 4% Uterine corpus Prostate 20% 7% Uterine corpus Prostate 10% Leukemia 4% Leukemia 4% 4% Leukemia 4% Non-Hodgkin Non-Hodgkin 5% Non-Hodgkin 4% 3% Non-Hodgkin lymphoma lymphoma lymphoma lymphoma All other sites 24% 21% All other sites All other sites 24% 23% All other sites Figure 7.17 Cancer incidence (A) and mortality (B) by site and sex. Excludes basal cell and squamous cell skin cancers and in situ carcinomas except urinary bladder. (Modified from Siegel RL, Miller KD, Jemal A: Cancer statistics, 2017, CA Cancer J Clin 67:7–30, 2017.) 278 CHAPTER 7 Neoplasia between 1990–1991 and 2004, lung cancer death rates in Alcohol consumption. Alcohol abuse increases the risk of women and liver and intrahepatic bile duct cancer death carcinoma of the oropharynx (excluding lip), larynx, and rates in men increased substantially, offsetting some of the esophagus and, by the development of alcoholic cirrhosis, improvement in survival from other cancers. Indeed, hepatocellular carcinoma. Moreover, the risk of cancers although carcinomas of the breast occur about 2.5 times in the upper airways and digestive tract imposed by more frequently than those of the lung in women, lung alcohol is increased synergistically when combined with cancer now causes more deaths in women. tobacco use. Race is not a discrete biologic variable, but it can define Diet. Although the precise dietary factors that affect cancer groups at risk for certain cancers. The disparity in cancer risk remain a matter of debate, wide geographic variation mortality rates between Americans who are Caucasian or in the incidences of colorectal carcinoma, prostate carci- of African descent persists, but African Americans had the noma, and breast carcinoma has been ascribed to differ- largest decline in cancer mortality during the past decade. ences in diet. People identifying as Hispanic living in the United States Obesity. Given that the obesity epidemic in the United have a lower frequency of the most common cancers affecting States is spreading to other parts of the world (Chapter the Caucasian non-Hispanic population and a higher 9), it is concerning that obesity is associated with increased incidence of cancers of the stomach, liver, uterine cervix, cancer risk. The most overweight individuals in the U.S. and gallbladder as well as certain leukemias. population have 52% (men) to 62% (women) higher death rates from cancer than do their slimmer counterparts; it Environmental Factors follows that approximately 14% of cancer deaths in men and 20% in women are associated with obesity. Although both genetic and environmental factors con- Reproductive history. Lifelong cumulative exposure to tribute, environmental influences are the dominant risk estrogen stimulation, particularly if unopposed by factors for most cancers. One line of evidence supporting this progesterone, increases the risk of cancers of the breast idea comes from longitudinal changes in cancer incidence and endometrium, tissues that are responsive to these in the United States. Examples include the tight tracking hormones. It is likely that some of the geographic variation of lung cancer incidence with changes in smoking habits in breast cancer incidence is related to differing cultural over time; the sharp drop in stomach cancer incidence mores that influence the timing and number of pregnan- during the 20th century, believed to stem from decreased cies a woman has during her lifetime. exposure to unknown environmental carcinogens; and a Environmental carcinogens. There is no paucity of well- recent increase in the incidence of liver cancer, which is characterized environmental carcinogens: they lurk in likely due to rising rates of chronic hepatitis B virus (HBV) the ambient environment, in the workplace (Table 7.3), and hepatitis C virus (HCV) infection and obesity. Other in food, and in personal practices. Individuals may be evidence is found in the wide geographic variation that exposed to carcinogenic factors when they go outside exists in the incidence of specific cancers (Fig. 7.18). For (e.g., ultraviolet [UV] rays, smog), drink well water (e.g., example, the most common cancer of men in the United arsenic, particularly in Bangladesh), take certain medica- States and in most other higher income countries is prostate tions (e.g., methotrexate), go to work (e.g., asbestos), or cancer, but in other countries or regions, cancers of the lounge at home (e.g., grilled meat, high-fat diet, alcohol). liver, stomach, esophagus, bladder, lung, oropharynx, and the immune system rise to the top of the list. Similarly, the It appears that almost everything one does to earn a incidence of breast cancer is generally much higher in women livelihood or for pleasure is fattening, immoral, illegal, or, living in higher income countries than in lower income even worse, carcinogenic! countries. Although racial predisposition may factor in, it is believed that environmental influences—some known, some Age not—underlie most of these differences in cancer incidence. Among the best-established environmental factors affect- Age has an important influence on the risk of cancer. Most ing cancer risk are the following. carcinomas occur in adults older than 55 years of age. Cancer Infectious agents. About 15% of all cancers worldwide are is the leading cause of death among women aged 40 to 79 caused directly or indirectly by infectious agents, with and among men aged 60 to 79; the decline in cancer deaths the burden of cancers linked to infections being roughly after age 80 is due to the lower number of individuals who three times higher in the developing world than in the reach this age. The rising incidence of cancer with age is developed world. For example, human papillomavirus likely explained by the accumulation of somatic mutations (HPV), an agent spread through sexual contact, has a that accompanies the aging of cells (discussed later). A decline causative role in the majority of cervical carcinomas and in immune competence in older individuals may also be a an increasing fraction of head and neck cancers. Specific factor. infectious agents and their associated cancers are discussed Tragically, children are not spared; cancer accounts for later in this chapter. approximately 10% of all deaths in children younger than Smoking. Cigarette smoking is the single most important age 15 in the United States, second only to accidents. environmental factor contributing to premature death However, the types of cancers that predominate in children in the United States. Smoking, particularly of cigarettes, are different from those seen in adults; in part, this is because is implicated in cancer of the mouth, pharynx, larynx, pediatric cancers are more likely to be caused by inherited esophagus, pancreas, and bladder and, most significantly, mutations (particularly in tumor suppressor genes, described in about 90% of lung cancers (Chapter 9). later) and much less likely to stem from exposure to  Epidemiology of cancer 279 A. Worldwide variation of cancer incidence in males Most common cancer: Prostate Lung and bronchus Stomach Liver Colon and rectum Kaposi sarcoma Esophagus Non-Hodgkin lymphoma Leukemia Oral cavity No data B. Worldwide incidence of breast cancer Rate per 100,000: ≥ 80.3 59.7 - 80.2 46.8 - 59.6 38.7 - 46.7 25.7 - 38.6 ≤ 25.6 No data Figure 7.18 Geographic variation in cancer incidence. (A) Most common cancers in men by country. (B) Variation in breast cancer incidence in women by country. (Modified from American Cancer Society: Global Cancer Facts & Figures, ed 3, Atlanta, 2015, American Cancer Society.) environmental carcinogens (e.g., cigarette smoking). This such as neuroblastoma, Wilms tumor, retinoblastoma, acute difference explains why carcinomas, which are frequently lymphoblastic leukemia, and rhabdomyosarcoma. These are caused by carcinogens and are the most common general discussed in Chapter 10 and elsewhere in the text. type of tumor in adults, are very rare in children. Instead, acute leukemia and distinctive neoplasms of the central Acquired Predisposing Conditions nervous system cause approximately 60% of childhood cancer deaths. The common neoplasms of infancy and Acquired conditions that predispose to cancer can be childhood include the so-called small round blue cell tumors divided into chronic inflammatory disorders, precursor 280 CHAPTER 7 Neoplasia Table 7.3 Occupational Cancers Human Cancers for Which Agents or Groups of Agents Reasonable Evidence Is Available Typical Use or Occurrence Arsenic and arsenic compounds Lung carcinoma, skin carcinoma By-product of metal smelting; component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips Asbestos Lung, esophageal, gastric, and colon Formerly used for many applications because of fire, heat, and carcinoma; mesothelioma friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing papers, and floor tiles Benzene Acute myeloid leukemia Principal component of light oil; despite known risk, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents; formerly widely used as solvent and fumigant Beryllium and beryllium compounds Lung carcinoma Missile fuel and space vehicles; hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors Cadmium and cadmium compounds Prostate carcinoma Uses include yellow pigments and phosphors; found in solders; used in batteries and as alloy and in metal platings and coatings Chromium compounds Lung carcinoma Component of metal alloys, paints, pigments, and preservatives Nickel compounds Lung and oropharyngeal carcinoma Nickel plating; component of ferrous alloys, ceramics, and batteries; by-product of stainless-steel arc welding Radon and its decay products Lung carcinoma From decay of minerals containing uranium; potentially serious hazard in quarries and underground mines Vinyl chloride Hepatic angiosarcoma Refrigerant; monomer for vinyl polymers; adhesive for plastics; formerly inert aerosol propellant in pressurized containers Modified from Stellman JM, Stellman SD: Cancer and workplace, CA Cancer J Clin 46:70, 1996. lesions, and immunodeficiency states. Chronic inflammatory gastritis with antibiotics can quell a chronic inflammatory disorders and precursor lesions span a diverse set of condi- condition that might otherwise lead to the development tions that are all associated with increased cellular replication, of a gastric cancer. which appears to create a “fertile” soil for the development Precursor lesions. Precursor lesions are defined by localized of malignant tumors. Indeed, repeated rounds of cell division morphologic changes that identify a field of epithelium may be required for neoplastic transformation, as proliferat- that is at increased risk for malignant transformation. ing cells are most at risk for somatic mutations that lead to These changes may take the form of hyperplasia, meta- carcinogenesis. Immunodeficiency states predispose to plasia, or dysplasia. The link between epithelial dysplasia virus-induced cancers. Each of these acquired predisposing and metaplasia with various forms of carcinoma has conditions is described next. already been mentioned. Precursor lesions consisting of Chronic inflammation. Virchow first proposed a cause- hyperplasias often stem from chronic exposure to trophic and-effect relationship between chronic inflammation factors. One of the most common precursors of this type and cancer in 1863. The scope of this association is now is endometrial hyperplasia, which is caused by sustained clear; cancer risk is increased in individuals affected by estrogenic stimulation of the endometrium. Other “at a wide variety of chronic inflammatory diseases, both risk” lesions consist of benign neoplasms. A classic lesion infectious and noninfectious (Table 7.4). Tumors arising of this type is the colonic villous adenoma, which progresses in the context of chronic inflammation are mostly carci- to cancer in about 50% of cases if left untreated. It should nomas, but also include mesothelioma and several kinds be emphasized, however, that most benign tumors of lymphoma. As with any cause of tissue injury, these transform rarely (e.g., uterine leiomyomas, pleomorphic disorders are accompanied by a compensatory prolifera- adenoma) and others not at all (e.g., lipomas). Why most tion of cells that serves to repair the damage. In some benign tumors have a negligible risk of malignant cases, chronic inflammation may increase the pool of transformation is an unsettled question; one possibility tissue stem cells, which may be particularly susceptible is that benign tumors at high risk for malignant trans- to transformation. Additionally, activated immune cells formation possess the cancer-enabling property of genomic produce reactive oxygen species that may damage DNA instability (discussed later), whereas other benign tumors and inflammatory mediators that may promote cell do not. survival, even in the face of genomic damage. Whatever Immunodeficiency and cancer. Patients who are immuno- the precise mechanism, the link between chronic inflam- deficient, particularly those with deficits in T-cell mation and cancer has practical implications. For instance, immunity, are at increased risk for cancer, especially diagnosis and effective treatment of Helicobacter pylori types caused by oncogenic viruses, presumably because  Molecular basis of cancer: role of genetic and epigenetic alterations 281 Table 7.4 Chronic Inflammatory States and Cancer with a well-defined inherited component, the risk of cancer Pathologic Associated Etiologic development may be greatly influenced by nongenetic Condition Neoplasm(s) Agent(s) factors. For instance, breast cancer risk in females who inherit Asbestosis, silicosis Mesothelioma, lung Asbestos fibers, silica mutated copies of the BRCA1 or BRCA2 tumor suppressor carcinoma particles genes (discussed later) has been observed to be almost Inflammatory bowel Colorectal carcinoma threefold higher for women born after 1940 than for women disease born before that year, perhaps because of changes in reproductive history. Conversely, genetic factors can alter Lichen sclerosis Vulvar squamous cell carcinoma the likelihood of cancers that are primarily induced by environmental carcinogens. This is because genetic variation Pancreatitis Pancreatic carcinoma Alcoholism, germline mutations (e.g., in (polymorphisms) in certain enzymes, such as the cytochrome the trypsinogen P-450 system, influences the conversion of procarcinogens gene) to active carcinogens. A cardinal example, discussed later, Chronic cholecystitis Gallbladder cancer Bile acids, bacteria, is a polymorphism in one of the P-450 genes that confers gallbladder stones susceptibility to smoking-induced lung cancer. Reflux esophagitis, Esophageal Gastric acid Barrett esophagus carcinoma Sjögren syndrome, MALT lymphoma KEY CONCEPTS Hashimoto thyroiditis EPIDEMIOLOGY OF CANCER Opisthorchis, Cholangiocarcinoma, Liver flukes The incidence of cancer varies with geography, age, race, and cholangitis colon carcinoma (Opisthorchis genetic background. Cancers are most common in adults older viverrini) than 55 years of age, but occur in adults at all ages and in Gastritis/ulcers Gastric Helicobacter pylori children and infants. The geographic variation is thought to adenocarcinoma, mainly stem from different environmental exposures. MALT lymphoma Important environmental factors implicated in carcinogenesis Hepatitis Hepatocellular Hepatitis B and/or C include infectious agents, smoking, alcohol, diet, obesity, reproduc- carcinoma virus tive history, and exposure to environmental carcinogens. Osteomyelitis Carcinoma in Bacterial infection The risk of cancer is increased by reparative proliferations draining sinuses caused by chronic inflammation or tissue injury, certain forms Chronic cervicitis Cervical carcinoma Human of hyperplasia, and immunodeficiency. papillomavirus Interactions between environmental factors and genetic factors Chronic cystitis Bladder carcinoma Schistosomiasis may be important determinants of cancer risk. MALT, Mucosa-associated lymphoid tissue. Modified from Tlsty TD, Coussens LM: Tumor stroma and regulation of cancer development, Ann Rev Pathol Mech Dis 1:119, 2006. MOLECULAR BASIS OF CANCER: ROLE OF GENETIC AND EPIGENETIC these individuals have a higher than normal incidence ALTERATIONS of chronic infection with viruses. These virus-associated tumors include lymphomas, certain carcinomas, and some Evidence for the genetic origins of cancer has been building sarcomas and sarcoma-like proliferations. The relationship for decades. However, a full accounting of the extent of between infections, immunity, and cancer is discussed these genetic aberrations is only now nearing completion, later in this chapter. made possible by technologic advances in DNA sequencing and other methods that permit genome-wide analysis of cancer cells. The complexity of these data is daunting, and Genetic Predisposition and Interactions Between the messages hidden within them have yet to be fully Environmental and Inherited Factors decoded, but certain “genomic themes” have emerged that are likely relevant to every cancer. In some families, cancer is an inherited trait, usually due Nonlethal genetic damage lies at the heart of carcinogenesis. to germline mutations in a tumor suppressor gene (described The initial damage (or mutation) may be caused by later). What then can be said about the influence of heredity environmental exposures, may be inherited in the germ- on sporadic malignant neoplasms, which constitute roughly line, or may be spontaneous and random, falling into 95% of cancers in the United States? While the evidence the category of “bad luck.” The term environmental, used suggests that these cancers are largely attributable to in this context, refers to any acquired mutation caused environmental factors or acquired predisposing conditions, by exogenous agents such as viruses or environmental lack of family history does not preclude an inherited com- chemicals or by endogenous products of cellular metabo- ponent. It is generally difficult to sort out hereditary and lism that have the potential to damage DNA (such as nonhereditary contributions because their interactions are reactive oxygen species) or alter gene expression through often complex, particularly when tumor development epigenetic mechanisms (e.g., so-called oncometabolites, depends on the action of multiple genes. Even in cancers described later). 282 CHAPTER 7 Neoplasia Accumulation of driver and passenger mutations Carcinogen-induced Additional driver Additional mutations, mutation mutations Emergence of subclones Diagnosis Normal Initiated precursor with Founding cell stem cell-like properties cancer cell Genetically heterogeneous cancer Acquisition of Further genetic Initiating mutation cancer hallmarks evolution Figure 7.19 Development of a cancer through stepwise acquisition of complementary mutations. The order in which various driver mutations occur in initiated precursor cells is not known and may vary from tumor to tumor. See text for details. A tumor is formed by the clonal expansion of a single precursor to as a mutator phenotype that is marked by genomic cell that has incurred genetic damage (i.e., tumors are clonal). instability. Alterations in DNA are heritable, being passed to daughter Carcinogenesis results from the accumulation of complementary cells, and thus all cells within an individual tumor share mutations in a stepwise fashion over time (Fig. 7.19). Malig- the same set of mutations that were present at the moment nant neoplasms have several phenotypic attributes of transformation. Such tumor-specific mutations are referred to as cancer hallmarks (discussed in detail later), most often identified by DNA sequencing (e.g., point such as excessive growth, local invasiveness, and the mutations) or by chromosomal analyses (e.g., chromo- ability to form distant metastases, which stem from somal translocations and copy number changes, discussed genomic alterations that change the expression and later). function of key genes and thereby impart a malignant Four classes of genes—growth-promoting proto-oncogenes, phenotype. growth-inhibiting tumor suppressor genes, genes that regulate Mutations that contribute to the acquisition of cancer programmed cell death (apoptosis), and genes that are respon- hallmarks are referred to as driver mutations. The first driver sible for DNA repair—are the principal targets of cancer- mutation that starts a cell on the path to malignancy is causing mutations. Mutations that activate proto-oncogenes the initiating mutation, which is typically maintained may either cause an increase in one or more normal in all the cells of the subsequent cancer. However, functions of the encoded gene product that promote because no single mutation appears to be fully trans- tumorigenesis or the appearance of a completely new forming, development of a cancer requires that the function that is oncogenic. Because these mutations cause “initiated” cell acquire a number of additional driver a “gain of function,” they can transform cells despite the mutations, each of which also contributes to the devel- presence of a normal copy of the same gene. Thus, in opment of the cancer. The time over which this occurs genetic parlance, oncogenes are dominant over their is unknown in most cancers, but appears to be lengthy; normal counterparts. Mutations that affect tumor sup- even in aggressive cancers that clinically seem to appear pressor genes generally cause a “loss of function,” and “out of the blue,” such as childhood acute lymphoblastic in most instances both alleles must be damaged before leukemia, cells bearing initiating mutations may be transformation can occur. As a result, mutated tumor found in blood samples taken as long as a decade before suppressor genes usually behave in a recessive fashion. diagnosis. The persistence of initiated cells during this However, there are exceptions: sometimes loss of only long preclinical prodrome is consistent with the idea a single tumor suppressor gene allele (a state termed that cancers arise from cells with stem cell–like proper- haploinsufficiency) reduces the quantity of the encoded ties, so-called cancer stem cells, that have a capacity for protein enough to release the brakes on cell proliferation self-renewal and long-term persistence. and survival. Such a finding indicates that two “doses” Loss-of-function mutations in genes that maintain genomic of the gene are essential for normal function. Apoptosis- integrity appear to be a common early step on the road to regulating genes may acquire abnormalities that result malignancy, particularly in solid tumors. Mutations that in less cell death and therefore enhanced survival. These lead to genomic instability not only increase the likeli- abnormalities include gain-of-function mutations in genes hood of acquiring driver mutations, but also greatly whose products suppress apoptosis and loss-of-function increase the frequency of mutations that have no mutations in genes whose products promote cell death. phenotypic consequence, so-called passenger mutations, Loss-of-function mutations affecting DNA repair genes which are much more common than driver mutations. contribute to carcinogenesis indirectly by impairing As a result, by the time a cell acquires all of the driver the ability of the cell to recognize and repair nonlethal mutations that are needed for malignant behavior, it genetic damage in other genes. As a result, affected cells may bear hundreds or even thousands of passenger acquire mutations at an accelerated rate, a state referred mutations.  Molecular basis of cancer: role of genetic and epigenetic alterations 283 Mutations in many other genes contribute to tumori- sequencing (Fig. 7.20). As predicted, two types of mutations genesis by interfering with host immune responses were identified in these studies: (1) mutations that are present or altering interactions with the stroma, or by other in all tumor sites tested, which were presuma